New Drugs In Hematology

Brentuximab Vedotin in Lymphomas

Anas Younes, M.D.

Chief, Lymphoma Service
Memorial Sloan-Kettering Cancer Center

Monday, May 9, 2016

9:15-9:45 a.m

U.S. Cancer Statistics 2016

300.000
249.260
224.390

200.000

180.890

Incidence
100.000

Death

95.270
76.960

72.580

30.330

18.960

8.500

Siegel R, et al, ACS 2016

1982, Nature: Schwab, Stein and Diehl:

Production of Ki-1 monoclonal antibody that detects CD30 on HRS cells

CD30

CD30 Expression
systemic anaplastic large cell lymphoma

Greg Hapgood, and Kerry J. Savage Blood 2015;126:17-25

1992 (Cell): Durkop and Stein:

Molecular cloning of CD30 = TNF receptor family member
1993 (Cell): Smith et al:
Molecular cloning of CD30L = TNF family member

Younes A , Kadin M E JCO 2003;21:3526-3534

Expression Pattern of CD30 and CD30L

Younes, A: Curr Opin Oncol. 2011 Nov;23(6):587-93

6

Overall survival rates for patients with Hodgkin

lymphoma
Initial Therapy

Post ASCT

MDACC (1944-2004)
N=2,723
TTR
>12 m
6-12 m
4-6 m
0-3 m

Fanale M and Younes, A et al, 2013

N Median OS (y)
172
4.6
165
2.4
204
1.5
215
0.7

Horning S et al, Ann Oncol 2008:19 (suppl 4):Abstract 118

Arai S et al. Leukaemia and Lymphoma. 2013. In print

Summary results of pahse I/II clinical trials

using naked antibodies targeting CD30

Drug

MDX-060
SGN-30
SGN-30
Xmab2513

Disease

Antibody
type

Phase

Number of
evaluable
patients

PR

CR

%PR + CR

HL, ALCL

Humanized

HL, ALCL

Chimeric

HL = 63
ALCL = 9
24

2
2
0

2
0
0

6%
22%
0

HL, ALCL

Chimeric

II

HL

Humanized

HL = 38
ALCL = 41
13

0
5
1

0
2
0

0
17%
7%

8
Younes, A: Curr Opin Oncol. 2011

Brentuximab vedotin: mechanism of action

Brentuximab vedotin (SGN-35) ADC
monomethyl auristatin E (MMAE), potent antitubulin agent
protease-cleavable linker
anti-CD30 monoclonal antibody

ADC binds to CD30

ADC-CD30 complex traffics to
lysosome

MMAE is released
MMAE disrupts
Microtubule network

G2/M cell
cycle arrest

Apoptosis

Younes A et al. N Engl J Med 2010; 363:1812-21 (appendix)

Phase I Study of Brentuximab Vedotin (SGN-35)

in Relapsed HL and ALCL
Treatment
Cycle 1
21 days
D1 dosing

Follow-up
Cycle 2
21 days

Restage*

Stable disease or better

may receive additional
cycles

D1 dosing

SGN-35 administered IV every 21 days

Dose cohorts: 0.1, 0.2, 0.4, 0.6, 0.8, 1.2, 1.8, 2.7, 3.6 mg/kg
* CT and PET scans were retrospectively reviewed by an independent review
facility (IRF)
Younes A, et al. N Engl J Med 2010; 363:1812-1821

Phase-I brentuximab vedotin in relapsed

CD30+ HL and ALCL
Treatment Response
Investigator Assessment

IRF Assessment

86% of patients achieved tumor reductions

83% of patients achieved tumor reductions

Younes A, et al. N Engl J Med 2010; 363:1812-1821

Brentuximab vedotin: Phase I trial

Phase I dose-escalation study in patients with relapsed or refractory
CD30+ lymphoma: best clinical response in 45 patients
Objective response rate (ORR) (CR+PR) = 38%; CR = 24%; SD = 43%; ORR in
patients receiving maximum tolerated dose 1.8 mg/kg = 50%
Dose (mg/kg)
0.6
0.8
1.2
(n=3)
(n=3)
(n=4)

0.1
(n=3)

0.2
(n=4)

0.4
(n=3)

Complete response (CR)

Partial response (PR)

Stable disease (SD)

Progressive disease (PD)

Could not be evaluated

Response

1.8
(n=12)

2.7
(n=12)

3.6
(n=1)

Tumour regression in 86%, with tumour-related symptoms resolved in 81% of patients

Median duration of objective response at least 9.7 months

Younes A et al. N Engl J Med 2010;363:18121821.

12

Phase I Brentuximab Vedotin in Relapsed HL

21-year-old female
HL diagnosed 2003
ABVD + XRT to mediastinum
ICE
BEAMASCT
HDAC-inhibitor

SGN-35 2.7 mg/kg x 8 cycles

Best clinical response: CR
CT 93% reduction, PET PET negative

Younes A, et al. N Engl J Med 2010; 363:1812-1821

Brentuximab vedotin: pivotal Phase II trial

102 patients with relapsed/refractory HL post-autologous stem cell
transplantation (ASCT)
Eligibility
Relapsed/refractory
CD30+ HL
Age 12 years
Measurable disease
1.5 cm
ECOG 01
Prior ASCT

Treatment (n=102)

Follow-up

Brentuximab vedotin
1.8 mg/kg by i.v. every
21 days
Administered outpatient
over 30 min
Maximum 16 cycles for
SD or better

Every
12 weeks

Restage at cycles
2, 4, 7, 10, 13, 16*

Younes A et al. J Clin Oncol 2012;30: 2183-9.

Phase II pivotal study of brentuximab vedotin

in relapsed HL post ASCT
ORR 75%
CR 34%

94% patients achieved tumour reduction

IRF independent review facility

Younes A et al. J Clin Oncol 2012;30: 2183-9.

brentuximab vedotin in relapsed or refractory HL

Long Term Follow-Up

CR: PFS

4/16 in CR had Allo SCT

Ajay K. Gopal et al. Blood 2015;125:1236-1243

ABVD vs. Stanford V

FFS

Gordon L I et al. JCO 2013;31:684-691

2013 by American Society of Clinical Oncology

OS

Phase 1 ABVD/AVD + brentuximab vedotin

Stage IIa bulky, IIB, III-IV

Cycle 1

Cycle 2

Cycle 3

Brentuximab Vedotin
A(B)VD
6 Cycles +/- XRT
0

10

12

Weeks

Younes A, Ansell S, et al, Lancet Oncology 2013

ABVD or AVD + Brentuximab Vedotin

Brentuximab vedotin + ABVD

N=25 total
Cohort 1 (0.6 mg/kg)
N=6
Cohort 2 (0.9 mg/kg)
N=13

Brentuximab vedotin + AVD

N=26 total

Cohort 3 (1.2 mg/kg)

N=6

Cohort 4 (1.2 mg/kg)

N=6

Expansion cohort (1.2 mg/kg)

N=20

Dose-limiting toxicities were defined as any Cycle 1 toxicity requiring 7day delay in ABVD or AVD
Study has completed enrollment
All patients in the AVD expansion cohort are currently receiving treatment

Brentuximab Vedotin + ABVD or AVD

Pulmonary Toxicity and Efficacy

Younes A, Ansell S, et al, Lancet Oncology 2013

Phase-I Brentuximab vedotin + AVD Advanced stage HL

3-Year follow up

FFS

OS

AVD+A n = 26 3-y FFS = 92%

1.0

AVD + A n = 26 3-y OS = 100%

1.0

.9

.9

.8
.7

ABVD+A n = 24 3-y FFS = 79%

Cum Survival

Survival

ABVD + A n = 24 3-y OS = 92%

.8

.6
.5
.4
.3

.7
.6
.5
.4
.3

.2

.2

.1

.1

0.0

0.0

10

15

20

25

30

35

FFS (mos)

40

45

50

55

60

10

15

20

25

30

35

40

45

50

55

60

OS (mos)

Connors J et al , ASH 2014

Randomized study in newly diagnosed advanced stage HL

Echelon-1

Stage III/IV HL

R
A
N
D
O
M
I
Z
E

ABVD x 6

AVD + brentuximab vedotin

E2496 Advanced Stage HL (ABVD/Stanford V)

Failure-free survival

60 yr

<60 yr

FFS
OS

3-year
5-year
3-year
5-year

Overall survival

<60 yr

< 60 years

=/> 60 years

76%
74%
93%
90%

56%
48%
70%
58%

0.002

60 yr

<0.0001
Evens AM et al. Brit J Haem 2013

Frontline brentuximab vedotin monotherapy in Hodgkin lymphoma

patients aged 60 years and older
ORR = 92% (CR= 73%, PR= 19%)
Patients Characteristics (N=26)
Median age (yrs), Range

78 (64-92)

Stage 3-4

63%

Bulky disease

22%

Not candidate for

combination chemo

52%

Median PFS = 10.5 months

Median PFS for CR = 11.8 months

Patients received a median of 8 cycles of brentuximab vedotin

(range, 3 to 23 months), with 4 patients completing 16 cycles and
1 patient completing 23 cycles.

Andres Forero-Torres et al. Blood 2015;126:2798-2804

ASCT for relapsed / refractory HL

ICE + ASCT

GVD + ASCT
GVD + ASCT

GVD post ASCT

Moskowitz C H et al. Blood 2001;97:616-623

Bartlett N et al. Ann Oncol 2007;18:1071-1079

Response adapted salvage therapy for

transplant eligible HL
27%
45 patients
Brentuximab Vedotin 1.2mg/kg

Qwk x 3 followed by 1 wk rest

Qwk x 3 followed by 1 wk rest

PETR
e
s
t
a
g
e

Stem cell collection

=> BEAM ASCT

73%
PET+

Augmented
ICE
69%

Overall 76% achieved PET-/CR and

proceeded to ASCT

PETStem cell collection

=> BEAM ASCT
Alison J Moskowitz , et al The Lancet Oncology, , 2015, 284 - 292

Tumour reduction after brentuximab vedotin

Data shows PET status according to the
Deauville scores of 15

Alison J Moskowitz , et al The Lancet Oncology, , 2015, 284 - 292

Brentuximab vedotin +/- AugICE for

relapsed HL
OS

EFS

EFS by PET and treatment

groups

Alison J Moskowitz , et al The Lancet Oncology, , 2015, 284 - 292

Brentuximab Vedotin as Second-Line Therapy

before Autologous Transplantation in
Relapsed/Refractory Hodgkin Lymphoma
Best response to
BV
(N=37)

Response to
chemotherapy after BV
(ICE/IGEV/GND)
(N=18)

Best response at
the time of ASCT
(n=33)

37

18

33

ORR

68%

89%

CR

35%

61%

73%

PR

32%

28%

27%

SD

27%

6%

3%

PD

5%

6%

Robert Chen, et al: Biology of Blood and Marrow Transplantation 2015

Brentuximab vedotin in pre-ASCT therapy

% CR

% CR with BV

Reference

ICE

97

60%

N/A

Mockowitz C, BLOOD 2012

BV->ICE

46

73%

27%

Moskowitz A, Lancet Oncol 2015

BV -> chemo

36

35%

Chen R, ASH 2014

BV+Benda

34

N/A

LaCasce A, ASH 2014

82%

Brentuximab Vedotin Plus Bendamustine: A Highly Active Salvage

Treatment Regimen for Patients with Relapsed or Refractory
Hodgkin Lymphoma
Ann S. LaCasce, MD1, Gregory Bociek2, Ahmed Sawas3, Paolo F. Caimi, MD4, Edward
Agura5, Jeffrey Matous6, Stephen Ansell, MD, PhD7, Howland Crosswell, MD8,
Miguel Islas-Ohlmayer9*, Caroline Behler10, Eric Cheung11*, Andres ForeroTorres12, Julie Vose2, Owen A. O'Connor, MD, PhD3*, Neil Josephson13 and Ranjana
Advani14

Benda + BV x up to 6

N=55 pts
ORR = 93%
CR = 74%

ASCT

BV x 16 doses

1-year PFS =
80%

ASH 2015

The AETHERA study

329 patients were randomised at 78 sites in North America and Europe

X 16

Moskowitz C, et al The Lancet 2015

Progression-free survival
PFS per Investigator

PFS per IRF

BV
(N=165)
Hazard Ratio (95% CI)

BV
(N=165)

Placebo
(N=164)

0.57 (0.400.81, P=0.001)

Placebo
(N=164)

Hazard Ratio (95% CI)

0.50 (0.360.70)

Events

60

75

Events

60

89

Median PFS (months)

43

24

Median PFS (months)

--

16

63%

51%

65%

45%

2-year PFS rate

2-year PFS rate

* Regularly scheduled CT scans

Includes information from both radiographic assessments and clinical lymphoma assessments
33

Moskowitz C, et al The Lancet 2015

systemic anaplastic large cell lymphoma

Greg Hapgood, and Kerry J. Savage Blood 2015;126:17-25

Brentuximab Vedotin: Relapsed / Refractory ALCL

Barbara Pro et al. JCO 2012;30:2190-2196

2012 by American Society of Clinical Oncology

Brentuximab Vedotin: Relapsed / Refractory ALCL

Response / Outcome

ORR
CR
Median DOR
Median DOR
(for patients who obtained CR)
Median PFS
Median OS
Median OS
(for patients who obtained CR)
Estimated 3-year survival
Pro B, et al. ASH Meeting 2013. Abstract 1809.

86%
59%
13.2 months
26.3 months
14.6 months
Not yet reached
7.7 months
63%

Brentuximab Vedotin: Relapsed / Refractory ALCL

Barbara Pro et al. JCO 2012;30:2190-2196

Brentuximab vedotin plus CHOP/CHP for

CD30+ PTCL phase I
Treatment schema

Patients ORR

CR

Sequential treatment:

13 ALCL

85%

62%

19 ALCL
7 non-ALCL

100%

88%

BV x2 -> CHOPx6 -> BV x8

Combination treatment
BV plus CHP x6 -> BV x 10

Notable grade 3 adverse events in combination arm:

Febrile neutropenia 31%
Peripheral sensory neuropathy 8%
Cardiac failure 8%
Michelle A. Fanale et al. JCO
2014;32:3137-3143

Phase 1 Trial Brentuximab Vedotin + CHP

Sequential Treatment
(med f/u 23.8 mo)
1 yr estimated PFS 77%

1 yr estimated OS 85%

Fanale M A et al. JCO

Combination Treatment
(med f/u 21.4 mo)
1 yr estimated PFS 71%

1 yr estimated OS 88%

Activity of Brentuximab Vedotin in

Relapsed CD30+ Lymphoma

Response Rate (%)

100
75
50
25
0

34/102

15/20

33/58

CR
PR

2/28

7/43
42/102

17/58

2/11
1/11

12/28
5/20

10/43

2/18
2/18

Objective responses in relapsed T-cell lymphomas

with single-agent brentuximab vedotin

Maximum tumor size decrease by

quantitative CD30 expression.

%ORR

%CR

All (n=34)

41%

23%

AITL (N=13)

54%

38%

PTCL (N=21)

33%

14%

PFS by histology

Steven M. Horwitz et al. Blood 2014;123:3095-3100

Retreatment with brentuximab vedotin in patients

with CD30-positive hematologic malignancies

Bartlett, N et al: Journal of Hematology & Oncology 2014, 7:24

CD30 : From a Biomarker to Therapeutic Target

J Immunolgy:
Hecht, Longo,
and Fisher
Production of
the HeFi antiCD30 antibody

Cell: Durkop and

Stein:
Molecular
cloning of
CD30 = TNF
receptor family
member

Nature: Schwab,
Stein and Diehl:
Production of Ki-1
monoclonal antibody
that detects
CD30 on HRS cells

1982

FDA approval
Brentuximab vedotin for
relapsed HL and sALCL

1985

1992 1993
Lancet: Falini et
al. First pilot
study (n=4) of
ADC- murine
anti-CD30 (BerH2) conjugated
to Saporin (SO6)

Cell: Smith :
Molecular
cloning of
CD30L = TNF
family member

2010 2011
NEJM: Younes, A.
Bartlett, N. L. Leonard, J.
P. Kennedy, D. A.Lynch,
C. M.Sievers, E. L.ForeroTorres, A:
Phase-I SGN35 published

43
Younes, A: Curr Opin Oncol. 2011 Nov;23(6):587-93